DESCRIPTION

Cysview contains hexaminolevulinate hydrochloride, an optical imaging drug
that in solution form is instilled intravesically for use with photodynamic
blue light cystoscopy as an adjunct to white light cystoscopy.

The chemical formula for hexaminolevulinate hydrochloride is C11H21NO3•HCl.
Its molecular weight is 251.76 and it has the following structural formula:

Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution is intended
for intravesical administration only after reconstitution with the supplied
50 mL DILUENT. Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution
and DILUENT for Cysview are supplied together as a kit.

The reconstituted solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) contains 2 mg/ml of hexaminolevulinate
hydrochloride and is colorless to pale yellow. It is free from visible particles
and has a pH between 5.7 and 6.2.

INDICATIONS

Cysview (hexaminolevulinate hydrochloride intravesical solution) is indicated for use in the cystoscopic detection of non-muscle invasive
papillary cancer of the bladder among patients suspected or known to have lesion(s)
on the basis of a prior cystoscopy. Cysview (hexaminolevulinate hydrochloride intravesical solution) is used with the Karl Storz D-Light
C Photodynamic Diagnostic (PDD) system to perform cystoscopy with the blue light
setting (Mode 2) as an adjunct to the white light setting (Mode 1).

Cysview (hexaminolevulinate hydrochloride intravesical solution) is supplied as a kit containing two vials: a clear glass vial labeled
as Cysview (hexaminolevulinate hydrochloride) for Intravesical Solution, containing
100 mg hexaminolevulinate hydrochloride as a powder, and a vial labeled as DILUENT
for Cysview (hexaminolevulinate hydrochloride intravesical solution) , containing 50 mL of the diluent in a polypropylene vial.

Perform all steps under aseptic conditions. Use gloves during the reconstitution
procedure; skin exposure to hexaminolevulinate hydrochloride may increase the
risk for sensitization to the drug.

Use a 50 mL syringe with a Luer Lock tip throughout the reconstitution procedure
to ensure that the correct concentration (2mg/mL) of the drug is obtained and
that a stable syringe-catheter connection is made for the bladder instillation
of Cysview (hexaminolevulinate hydrochloride intravesical solution) .

Figure1

1. Remove the cap from the sterile 50 mL syringe and carefully retain it for
subsequent reattachment to the syringe (step 4). Attach a needle to the syringe
and withdraw 50 mL of the diluent (Figure 1).

Figure 2

2. Penetrate the stopper of the Cysview (hexaminolevulinate hydrochloride intravesical solution) powder vial with the needle and inject
10 mL of the diluent from the syringe into the powder vial (Figure 2).

3. Without withdrawing the needle from the vial, hold the powder vial and syringe
in a firm grip (Figure 3) and gently shake to dissolve of the powder in the
diluent. The powder normally dissolves almost immediately.

Figure 3

4. Withdraw all of the dissolved solution from the powder vial (10 mL) into
the 50 mL syringe (Figure 4).

Figure 4

5. Remove the needle from the powder vial, disconnect the needle from the syringe
tip and discard it. Plug the syringe with the syringe cap (Figure 5). Gently
mix the contents of the syringe. The reconstituted solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) is colorless
to pale yellow and clear to slightly opalescent, and free from visible particles.

Figure 5

Figure 6

6. Peel off the detachable portion of the label (starting at the corner marked
with a black triangle) from the Cysview (hexaminolevulinate hydrochloride intravesical solution) powder vial and affix it to the syringe
containing the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) (Figure 6). Add two hours to the present
time and write the resulting expiration time and date on the syringe label.

Cysview (hexaminolevulinate hydrochloride intravesical solution) is now reconstituted and ready for use. Instill the reconstituted solution
of Cysview (hexaminolevulinate hydrochloride intravesical solution) into the bladder. If unable to administer the solution shortly after
reconstitution, the solution may be stored for up to 2 hours in a refrigerator
at 2°-8°C (36°- 46°F) in the labeled syringe. If not used within
2 hours, discard the solution.

For bladder instillation of the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) , use straight, or intermittent,
urethral catheters with a proximal funnel opening that will accommodate the
Luer Lock adapter. Use only catheters made of vinyl (uncoated or coated with
hydrogel), latex (amber or red), and silicone to instill the reconstituted Cysview (hexaminolevulinate hydrochloride intravesical solution) .
Do not use catheters coated or embedded with silver or antibiotics. In-dwelling
bladder catheters (Foley catheters) may be used if the catheters are inserted
shortly prior to Cysview (hexaminolevulinate hydrochloride intravesical solution) administration and are removed following the Cysview (hexaminolevulinate hydrochloride intravesical solution)
instillation.

Use the following steps for bladder instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) :

1. Using standard sterile catheterization technique, first insert the urethral
catheter into the bladder of the patient and use the catheter to completely
empty the patient's bladder before instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) .

Figure 7

2. To attach the syringe containing the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) to the catheter,
do the following:

Remove the syringe cap from the 50 mL syringe that contains the solution
of Cysview (hexaminolevulinate hydrochloride intravesical solution) .

Attach the Luer Lock end of the (provided) catheter adapter to the syringe.

Insert the tapered end of the catheter adapter into the funnel opening of
the catheter. See Figure 7, with the connection enlarged in the inset.

3. Slowly instill the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) into the bladder through the catheter
(Figure 7), ensuring that the complete volume of the syringe (50 mL) is administered.

4. After the solution is instilled, remove the catheter and instruct the patient
to retain the solution within the bladder for at least 1 hour; do not exceed
3 hours. Patients may stand, sit and
move about during the time period between instillation and start of the cystoscopic
procedure.

5. Evacuate the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) from the bladder as part of routine emptying
of the bladder immediately prior to the initiation of the cystoscopic procedure
(refer to the Karl Storz PDD Telescope Instruction manual). Also, the patient
may void and completely empty the bladder prior to the procedure.

Avoid skin contact with Cysview (hexaminolevulinate hydrochloride intravesical solution) . If skin does come in contact with Cysview (hexaminolevulinate hydrochloride intravesical solution) ,
wash immediately with soap and water and dry off. After voiding the bladder
of Cysview (hexaminolevulinate hydrochloride intravesical solution) , routinely wash the patient's perineal skin region with soap and
water and dry.

Use of the Karl Storz D-Light C Photodynamic Diagnostic (PDD) System

Cysview (hexaminolevulinate hydrochloride intravesical solution) imaging requires the use of the Karl Storz D-Light C PDD system, which
consists of a light source, a camera and a telescope. The light source enables
both white light cystoscopy and blue light (wavelength 360 – 450 nm) fluorescence
cystoscopy. Familiarity with this system is essential before beginning the procedure
and before instilling Cysview (hexaminolevulinate hydrochloride intravesical solution) into the bladder. For system set up and general
information for the safe use of the PDD system, refer to the Karl Storz instruction
manual for the PDD system and the instruction manuals for each of the system
components. The PDD System is not for use by healthcare providers with green-red
color blindness.

Cystoscopic Examination

Training

Training and proficiency in cystoscopic procedures are essential prior to the
use of Cysview (hexaminolevulinate hydrochloride intravesical solution) . Carefully review the instruction manuals provided with the Karl
Storz D-Light C Photodynamic Diagnosis (PDD) System. For additional training
in the use of the PDD System, contact the manufacturer's representative.

Preparation for Cystoscopy

Initiate the cystoscopic examination within 30 minutes after evacuation of
Cysview (hexaminolevulinate hydrochloride intravesical solution) from the bladder, but no less than 1 or more than 3 hours after Cysview (hexaminolevulinate hydrochloride intravesical solution)
is instilled in the bladder. If the patient did not retain Cysview (hexaminolevulinate hydrochloride intravesical solution) in the bladder
for 1 hour, allow 1 hour to pass from the instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) into the bladder
to the start of the cystoscopic examination. The efficacy of Cysview (hexaminolevulinate hydrochloride intravesical solution) has not
been established when the solution was retained for less than 1 hour.

Cystoscopic Examination

Empty the patient's bladder and then fill the bladder with a clear fluid (standard
bladder irrigation fluid) in order to distend the bladder wall for cystoscopic
visibility. Ensure adequate irrigation during examination of the bladder; blood, urine or floating particles in the bladder may interfere with visualization
under both white light and blue light.

First perform a complete cystoscopic examination of the entire bladder under
white light (Mode 1) and then repeat the examination of the entire bladder surface
under blue light (Mode 2) unless the white light cystoscopy reveals extensive
mucosal inflammation. Do not perform the blue light cystoscopy if the white
light cystoscopy reveals wide-spread mucosal inflammation. Abnormalities of
the bladder mucosa during blue light cystoscopy are characterized by the detection
of red, homogenous and intense fluorescence. The margins of the abnormal lesions
are typically well-demarcated and in contrast to the normal urothelium, which
appears blue. Register and document (map) the location and appearance (e.g.
papillary) of suspicious lesions and abnormalities seen under either white or
blue light.

During the cystoscopic examination, be aware that:

a red fluorescence is expected at the bladder outlet and the prostatic urethra;
this fluorescence occurs in normal tissue and is usually less intense and
more diffuse than the bladder mucosal fluorescence associated with malignant
lesions.

tangential light may give false fluorescence. To help avoid false fluorescence,
hold the endoscope perpendicular and close to the bladder wall with the bladder
distended.

malignant lesions may not fluoresce following Cysview (hexaminolevulinate hydrochloride intravesical solution) administration, particularly
if the lesions are coated with necrotic tissue. Blue light may fail to detect
T2 tumors which have a tendency to be necrotic on the surface, and necrotic
cells generally do not fluoresce [see WARNINGS AND PRECAUTIONS].

when performing the blue light cystocopy, avoid prolonged blue light exposure.
Studies have not evaluated the potential for adverse effects from blue light.
In the controlled clinical trial, the cumulative blue light exposure from
bladder mapping did not exceed 12 minutes and checking for complete tumor
resection under blue light did not exceed 8 minutes for any patient [see Clinical
Studies].

Perform biopsy and/or resection of suspicious lesions by transurethral resection
of the bladder (TURB) only after completing white and blue light cystoscopic
examinations with bladder mapping. Using standard cystoscopic practices, obtain
biopsies of abnormal areas identified during either white or blue light examination
and perform resections. Always check for the completeness of the resections
under both white light and blue light before finalizing the TURB procedure.

HOW SUPPLIED

Dosage Forms And Strengths

Cysview (hexaminolevulinate hydrochloride) is supplied as a kit containing:

Storage

Store Cysview (hexaminolevulinate hydrochloride) Kit for Intravesical Solution
at 20°-25°C (68°-77°F); excursions are permitted to 15°-30°C
(59°-86°F). Do not use beyond the expiry date printed on the carton.

Use the solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) shortly after reconstitution. If unable to use
within this time period, the reconstituted solution can be stored under refrigeration
(2°-8°C / 36°-46°F) for up to 2 hours in the 50 mL labeled syringe.

SIDE EFFECTS

Anaphylaxis has been reported following exposure to Cysview [see WARNINGS AND PRECAUTIONS].

Clinical Study Experience

Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in the clinical trials of a drug cannot be directly
compared to rates in the clinical trials of another drug and may not reflect
the rates observed in practice.

In six clinical trials, safety data were obtained from 1,324 patients, aged
32 to 96 years with a median age of 69 years, all primarily Caucasian and approximately
75% male. All patients were evaluated after a single instillation of 50 mL solution
of Cysview (hexaminolevulinate hydrochloride intravesical solution) . Of these patients, 161 (12.2%) patients reported at least one adverse
reaction. The most common adverse reaction was bladder spasm (reported in 2.2%
of the patients) followed by dysuria, hematuria, and bladder pain. No patients
experienced anaphylaxis. In the controlled clinical study, adverse reactions
were similar in nature and rate between the study drug group and the control
group [see Clinical Studies].

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain
size, it is not always possible to reliably estimate their frequency or establish
a causal relationship to drug exposure.

DRUG INTERACTIONS

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Anaphylaxis

Anaphylaxis, including anaphylactoid shock, has been reported following administration
of Cysview [see ADVERSE REACTIONS]. Prior to and during use of the Cysview (hexaminolevulinate hydrochloride intravesical solution) ,
have trained personnel and therapies available for the treatment of anaphylaxis.
The safety of repetitive Cysview (hexaminolevulinate hydrochloride intravesical solution) exposures has not been evaluated.

Failed Detection

Cysview (hexaminolevulinate hydrochloride intravesical solution) may fail to detect some bladder tumors, including malignant lesions.
Cysview (hexaminolevulinate hydrochloride intravesical solution) is not a replacement for random biopsies or any other procedure usually
performed in the cystoscopic evaluation for cancer. In the controlled clinical
trial, Cysview (hexaminolevulinate hydrochloride intravesical solution) failed to detect 10% of lesions confirmed as malignant within
the study drug group [see Clinical Studies]. Do not perform cystoscopy
with blue light alone as malignant lesions can be missed unless the bladder
is initially examined under white light [see DOSAGE AND ADMINISTRATION].

False Fluorescence

Fluorescent areas detected during blue light cystoscopy may not indicate a
bladder mucosal lesion. In the controlled clinical study, biopsies from one
of every four fluorescent areas showed neither dysplasia nor carcinoma, if the
areas were not also identified during white light cystoscopy [see Clinical
Studies]. In addition to these false detections, fluorescent areas within
the bladder mucosa may result from inflammation, cystoscopic trauma, scar tissue
or bladder mucosal biopsy from a previous cystoscopic examination.

The presence of urine and/or blood within the bladder may interfere with the
detection of tissue fluorescence. To enhance the diagnostic utility of Cysview (hexaminolevulinate hydrochloride intravesical solution)
with the Karl Storz D-Light C PDD System:

ensure the bladder is emptied of urine prior to the instillation of fluids
at cystoscopy;

biopsy/resect bladder mucosal lesions only following completion of both
white light and blue light cystoscopy;

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies in animals have been conducted to evaluate the carcinogenic potential
of hexaminolevulinate hydrochloride.

Hexaminolevulinate hydrochloride was not mutagenic in in vitro reverse
mutation tests in bacteria, or in chromosome aberration tests in human peripheral
blood lymphocytes, and was negative in an in vivo micronucleus test in mice
after intravenous injection of doses up to 45 mg/kg in the absence of light
activation. Adequate studies have not been performed to evaluate the genetic
toxicity of hexaminolevulinate hydrochloride in the presence of light activation.

Adequate reproductive and developmental toxicity studies in animals have not
been performed to evaluate the effects of hexaminolevulinate hydrochloride on
fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Adequate
reproductive and developmental toxicity studies in animals have not been performed.
Cysview (hexaminolevulinate hydrochloride intravesical solution) should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.

Nursing Mothers

It is not known whether hexaminolevulinate is excreted in human milk. Because
many drugs are excreted in human milk, exercise caution when Cysview (hexaminolevulinate hydrochloride intravesical solution) is administered
to nursing mothers.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of 1823 subjects in clinical studies of Cysview (hexaminolevulinate hydrochloride intravesical solution) , 67% were 65 years and over
while 34% were 75 years and over. No clinically important differences in safety
or efficacy have been observed between older and younger patients in the controlled
study.

OVERDOSE

No adverse events were reported in a dose-finding study conducted among patients
whose bladders were instilled with twice the recommended concentration (dose)
of solution of Cysview (hexaminolevulinate hydrochloride intravesical solution) .

CLINICAL PHARMACOLOGY

Mechanism of Action

Cysview (hexaminolevulinate hydrochloride intravesical solution) is an ester of the heme precursor, aminolevulinic acid. After bladder
instillation, Cysview (hexaminolevulinate hydrochloride intravesical solution) enters the bladder mucosa and is proposed to enter the
intracellular space of mucosal cells where it is used as a precursor in the
formation of the photoactive intermediate protoporphyrin IX (PpIX) and other
photoactive porphyrins (PAPs). PpIX and PAPs are reported to accumulate preferentially
in neoplastic cells as compared to normal urothelium, partly due to altered
enzymatic activity in the neoplastic cells. After excitation with light at wavelengths
between 360 and 450 nm, PpIX and other PAPs return to a lower energy level by
fluorescing, which can be detected and used for cystoscopic detection of lesions.
The fluorescence from tumor tissue appears bright red and demarcated, whereas
the background normal tissue appears dark blue. Similar processes may occur
in inflamed cells.

Pharmacodynamics

In vitro studies have shown increased porphyrin fluorescence in normal
urothelium after exposure to Cysview (hexaminolevulinate hydrochloride intravesical solution) . In the human bladder, a greater accumulation
of porphyrins is proposed in neoplastic or inflamed cells, compared to normal
urothelium. After bladder instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) for approximately 1 hour and
subsequent illumination with blue light at wavelengths 360 – 450nm, the porphyrins
will fluoresce red [see DOSAGE AND ADMINISTRATION].

Animal Toxicology and/or Pharmacology

Dose dependent neurological effects such as tremor, increased motor activity,
and increased startle and touch escape responses were observed immediately after
dosing at doses ≥ 30 mg/kg (24 times human systemic exposure based on the
body surface area, using 10% as the upper level of 90% confidence interval of
bioavailability) in a single dose rat study. The animals recovered to normal
status by 60 min after dosing. Adverse neurological effects were also noted
in other single or repeat dose toxicity studies.

Hexaminolevulinate hydrochloride had moderate to strong potential to cause
skin sensitization based on a local lymph node assay in mouse.

Clinical Studies

The safety and efficacy of Cysview (hexaminolevulinate hydrochloride intravesical solution) when used with photodynamic cystoscopy were
studied in a prospective, multicenter, controlled clinical trial. Adult patients
with known or suspected bladder cancer were randomized to either white light
(WL) cystoscopy (control group, n = 384) or WL followed by blue light (BL) cystoscopy
(study drug group, n = 395). Only the study drug group patients received Cysview (hexaminolevulinate hydrochloride intravesical solution)
by bladder instillation prior to cystoscopy. After bladder evacuation of Cysview (hexaminolevulinate hydrochloride intravesical solution) ,
bladder lesion mapping was performed initially using the Karl Storz PDD system
in the WL mode followed by lesion mapping in the BL mode. Control group patients
underwent only WL cystoscopy with lesion mapping. The average age of the randomized
patients was 69 years (range 24 to 96); 78% were male and 94% were Caucasian.
All patients had previously undergone cystoscopy.

The main diagnostic efficacy outcome was assessed within the study drug group.
This assessment compared lesions detected during an initial cystoscopic examination
to their centralized histologic findings (the standard of truth). Following
the initial diagnostic cystoscopy, patients within both study groups who had
histologically confirmed Ta and/or T1 lesions underwent follow-up WL cystoscopy
at 3, 6 and 9 months; these histologic evaluations were based upon the site
assessments at both the initial and follow-up cystoscopy.

Diagnostic efficacy assessed the number of patients within the study drug group
who had at least one additional Ta or T1 bladder cancer detected only by BL;
the proportion of these patients was compared to a proposed threshold proportion
of 10%. Within the study drug group, 286 patients had at least one Ta and/or
T1 lesion, including 47 patients who had at least one of the lesions detected
only by BL (see Table 1).

Among the lesions detected only by BL, 23% were negative for any carcinoma-related
pathology, including dysplasia. Among the lesions detected only by WL, 17% were
negative for any carcinoma-related pathology, including dysplasia.

Inform patients that Cysview (hexaminolevulinate hydrochloride intravesical solution) should be retained in the bladder for 1 hour from
instillation of Cysview (hexaminolevulinate hydrochloride intravesical solution) to the start of the cystoscopic procedure. If the patient
cannot hold Cysview (hexaminolevulinate hydrochloride intravesical solution) for 1 hour, but needs to void and expel Cysview (hexaminolevulinate hydrochloride intravesical solution) from the
bladder, he or she may void and should then inform a health care professional
[see DOSAGE AND ADMINISTRATION].

Report Problems to the Food and Drug Administration

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.